The human farnesyl pyrophosphate synthase (hFPPS) enzyme is responsible for the catalytic elongation of dimethylallyl pyrophosphate (DMAPP) to geranyl pyrophosphate (GPP) and then to farnesyl pyrophosphate (FPP) via the successive condensation of two isopentenyl pyrophosphate IPP units (Scheme 1).
Furthermore, farnesyl pyrophosphate (FPP) is the key metabolic precursor for the biosynthesis of geranylgeranyl pyrophosphate (GGPP), which is catalyzed by geranylgeranyl pyrophosphate synthase (GGPPS). Consequently, inhibition of FPPS would result in decreased levels of both FPP and GGPP in a mammalian host, including a human host. Post-translational prenylation with FPP or GGPP of conserved cysteine residues at (or near) the C-termini of over 300 known human proteins plays a crucial for their biological activity.

The farnesylation or geranylgeranylarion of proteins confers membrane localization, promotes specific protein-protein interactions and is believed to play a critical role in intracellular trafficking and signal transduction (see for example Nguyen U. T. T. et al. Nat. Chem. Biol. 2009, 5, 227-235 and Walsh C. T. et al. Angew. Chem. Int. Ed. 2005, 44, 7342-7372). Addition of the FPP or GGPP lipidic moiety to the GTP-binding proteins, including Ras, Rho, Rac and Rap, is also required in order to regulate the proliferation, invasive properties, and pro-angiogenic activity in human cancers (see Caraglia, M. et al. Endocrine-Related Cancer 2006, 13, 7-26 and Zhang, Y. et al. J. Am. Chem. Soc. 2009, 131, 5153-5162).
The role of hFPPS in protein prenylation in osteoclasts is known (see for example Dunford, J. E. et al. J. Pharmacol. Exp. Ther. 2001, 296, 235-242; Marma, M. S. et al. J. Med. Chem. 2007, 50, 5967-5975. Dunford, J. E. et al. J. Med. Chem. 2008, 51, 2187-2195) and nitrogen-containing bisphosphonate (N-BP) inhibitors of hFPPS are commonly used in the treatment of osteoporosis, tumor-induced hypercalcemia, Paget's disease and osteolytic metastases (see Caraglia, M. et al, supra).
Inhibitors of hFPPS have also been reported to stimulate the immune system by indirectly activating Vγ2Vδ2 T cells (also known as Vγ9Vδ2 T cells), thus mediating antitumor and antimicrobial effects, more specifically broad-spectrum antiviral and antibacterial effects (see for example Sanders, J. M. et al. J. Med. Chem. 2004, 47, 375-384; Zhang, Y. et al. J. Med. Chem. 2007, 50, 6067-6079; Morita, C. T. et al. Immunological Reviews 2007, 215, 59-76; Breccia, P. et al. J. Med. Chem. 2009, 52, 3716-3722 and Li, J. et al. J. Immunol. 2009, 182, 8118-8124. Evidence for the stimulation of Vγ2Vδ2-bearing T cells by N-BPs has been observed in multiple myeloma (MM) patients (Kunzmann, V.; Bauer, E.; Wilhelm, M. New Engl. J Med. 1999, 340, 737) and prostate cancer patients (Naoe, M.; Ogawa, Y.; Takeshita, K.; Morita, J.; Shichijo, T.; Fuji, K.; Fukagai, T.; Iwamoto, S.; Terao, S. Oncology, Res. 2010, 18, 493) treated with N-BPs. The antitumor effects of bisphosphonates inhibiting hFPPS (and/or its related enzyme hGGPPS) have been implicated in a variety of cancers (see Caraglia, M. et al, supra), including colorectal (see Notarnicola, M. et al. Oncology 2004, 67, 351-358), prostate, melanoma (see Laggner, U. et al. Clin. Immunol. 2009, 131, 367-373), breast (see for example Coleman, R. E. Eur. J. Cancer 2009, 45, 1909-1915), ovarian, and brain (see Ellis, C. A. et al. Proc. Natl. Acad. Sci. USA 2002, 99, 9876-9881) cancers.
In addition, current literature strongly suggests that the prenylation pathway leading from FPP to the prenylation of the small GTPase protein RhoA-cdc42, leads to accumulation of the phospho-Tau protein in the human brain, which is implicated in neuronal damage and the progression of Alzheimer's disease (AD) (see Eckert, G. P. et al. Neurobiol. Disease 2009, 35, 252; Hooff, G. P. et al. Biochim. Biophys. Acta 2010, 1801, 896; Chauhan, N. B. J. Ethnopharmacol. 2006, 108, 385; Ohm, T. G. et al. Pharmacopsychiatry 2003b, 36 Suppl 2, S120; Sayas, C. L. et al. J Biol. Chem. 1999, 274, 37046.)
Bisphosphonates of this disclosure that target the human FPPS may also be used for lowering cholesterol. However, such compounds may also be capable of inhibiting the FPPS enzymes of microorganisms and protozoan parasites, such as the groups of Leishmania, Plasmodium, Trypanosoma, Toxoplasma, Cryptosporidium. 